Abstract
The ability of proteins to sense membrane curvature is essential to cellular function. All known sensing mechanisms rely on protein domains with specific structural features such as wedge-like amphipathic helices and crescent-shaped BAR domains. Yet many proteins that contain these domains also contain large intrinsically disordered regions. Here we report that disordered domains are themselves potent sensors of membrane curvature. Comparison of Monte Carlo simulations with in vitro and live-cell measurements demonstrates that the polymer-like behavior of disordered domains found in endocytic proteins drives them to partition preferentially to convex membrane surfaces, which place fewer geometric constraints on their conformational entropy. Further, proteins containing both structured curvature sensors and disordered regions are more than twice as curvature sensitive as their respective structured domains alone. These findings demonstrate an entropic mechanism of curvature sensing that is independent of protein structure and illustrate how structured and disordered domains can synergistically enhance curvature sensitivity.
Highlights
The ability of proteins to sense membrane curvature is essential to cellular function
In each case we find a substantial increase in binding as membrane curvature increases, the level of which is comparable to the established structure-based curvature sensors, ENTH and N-terminal crescent-shaped BAR domain (N-BAR)
Comparing the curvature sensitivity of hisAP180CTD and wild-type Epsin N-terminal Homology domain (wt-ENTH) under these conditions reveals that they achieve 10-fold and 8-fold greater binding density to 20 nm vesicles in comparison to 200 nm vesicles, respectively. These results demonstrate that the intrinsically disordered protein (IDP) domain of AP180 has a similar sensitivity to membrane curvature in comparison to wt-ENTH, an established structure-based sensor of membrane curvature
Summary
The ability of proteins to sense membrane curvature is essential to cellular function. Comparison of Monte Carlo simulations with in vitro and live-cell measurements demonstrates that the polymer-like behavior of disordered domains found in endocytic proteins drives them to partition preferentially to convex membrane surfaces, which place fewer geometric constraints on their conformational entropy Proteins containing both structured curvature sensors and disordered regions are more than twice as curvature sensitive as their respective structured domains alone. Two primary mechanisms of curvature sensing have been wellcharacterized: (i) membrane scaffolding by crescent-shaped BAR (Bin/Amphiphysin/Rvs) domains[4], which match their curvature to that of the membrane, and (ii) detection of membrane defects by amphipathic helices[5], which insert like wedges between the head groups of lipids found in highly curved membrane surfaces Both of these mechanisms rely on specific protein structural features. This work necessitates a substantial expansion and reexamination of the set of proteins responsible for sensing the curvature of membrane structures in diverse biological processes
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